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Andreas Schedl - One of the best experts on this subject based on the ideXlab platform.
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A cell-autonomous role for WT1 in regulating Sry in vivo
Human molecular genetics, 2009Co-Authors: Stephen T Bradford, Dagmar Wilhelm, Roberto Bandiera, Valerie Vidal, Andreas Schedl, Peter KoopmanAbstract:Human patients with Frasier Syndrome express reduced levels of the +KTS isoforms of the developmental regulator WT1 and exhibit complete XY gonadal dysgenesis and male-to-female sex reversal. Mice with a targeted mutation that blocks production of these isoforms show a reduction in Sry mRNA in the gonad, but the molecular and cellular basis of this reduction has not been established. Using immunofluorescence analysis, we found a significantly lower level of SRY protein per cell in XY Wt1(+KTS)-null mouse gonads. We also found a reduced number of SRY-expressing cells, correlating with a decrease in cell proliferation at and near the coelomic epithelium at 11.5 dpc. No reduction in somatic cell numbers was seen in XX Wt1(+KTS)-null gonads, indicating that the effect of WT1 on cell proliferation is mediated by Sry. Sertoli cell differentiation was blocked in XY Wt1(+KTS)-null mouse gonads, as indicated by the loss of SOX9 and Fgf9 expression, but the addition of recombinant FGF9 to ex vivo gonad cultures rescued the mutant phenotype, as indicated by the induction of the Sertoli-cell specific marker anti-Müllerian hormone. Our data suggest that WT1(+KTS) is involved in the cell-autonomous regulation of Sry expression, which in turn influences cell proliferation and Sertoli cell differentiation via FGF9. Thus, sex reversal in Wt1(+KTS)-null mice and Frasier Syndrome patients results from a failure of Sertoli cells both to fully differentiate and to reach sufficient numbers to direct testis development.
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A novel Wilms’ tumor 1 gene mutation in a child with severe renal dysfunction and persistent renal blastema
Pediatric Nephrology, 2008Co-Authors: Nicole Wagner, Andreas Schedl, Kay-dietrich Wagner, Mickael Afanetti, Fabien Nevo, Corinne Antignac, Jean-francois Michiels, Etienne BerardAbstract:The Wilms’ tumor suppressor gene WT1 is an important regulator of development. Mutations in this gene have been associated with Wilms’ tumor, Frasier Syndrome, and Denys–Drash Syndrome, as well as isolated glomerular disease. Here we report the case of a 4-month-old girl, who presented with end-stage renal disease, thrombopenia, anemia, and cardiac hypertrophy accompanied by severe hypertension. Histological analysis of kidney biopsies revealed a massive and diffuse nephroblastomatosis with a dramatic reduction in the number of glomeruli. Although no normal cortical nephrons could be detected, medullary organization was nearly normal. Sequence analysis demonstrated a heterozygous nonsense mutation in exon 9 of WT1 , which leads to a truncation of the WT1 protein at the beginning of zinc finger 3. Given the requirement of WT1 for normal development of the kidney and heart, these data raise the hypothesis that the mutation identified was responsible for the severe phenotype observed in our patient.
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A novel Wilms’ tumor 1 gene mutation in a child with severe renal dysfunction and persistent renal blastema
Pediatric nephrology (Berlin Germany), 2008Co-Authors: Nicole Wagner, Andreas Schedl, Kay-dietrich Wagner, Mickael Afanetti, Fabien Nevo, Corinne Antignac, Jean-francois Michiels, Etienne BerardAbstract:The Wilms' tumor suppressor gene WT1 is an important regulator of development. Mutations in this gene have been associated with Wilms' tumor, Frasier Syndrome, and Denys-Drash Syndrome, as well as isolated glomerular disease. Here we report the case of a 4-month-old girl, who presented with end-stage renal disease, thrombopenia, anemia, and cardiac hypertrophy accompanied by severe hypertension. Histological analysis of kidney biopsies revealed a massive and diffuse nephroblastomatosis with a dramatic reduction in the number of glomeruli. Although no normal cortical nephrons could be detected, medullary organization was nearly normal. Sequence analysis demonstrated a heterozygous nonsense mutation in exon 9 of WT1, which leads to a truncation of the WT1 protein at the beginning of zinc finger 3. Given the requirement of WT1 for normal development of the kidney and heart, these data raise the hypothesis that the mutation identified was responsible for the severe phenotype observed in our patient.
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Two Splice Variants of the Wilms' Tumor 1 Gene Have Distinct Functions during Sex Determination and Nephron Formation
Cell, 2001Co-Authors: Annette Hammes, Marie-claire Gubler, Jian-kan Guo, Gudrun Lutsch, Joerg-robert Leheste, Danilo Landrock, Ulrike Ziegler, Andreas SchedlAbstract:Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier Syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.
Marie-claire Gubler - One of the best experts on this subject based on the ideXlab platform.
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wt1 and glomerular diseases
Pediatric Nephrology, 2006Co-Authors: Patrick Niaudet, Marie-claire GublerAbstract:The WT1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development and, when mutated, in the occurrence of kidney tumor and glomerular diseases. Patients with Denys-Drash Syndrome present with early nephrotic Syndrome with diffuse mesangial sclerosis progressing rapidly to end-stage renal failure, male pseudohermaphroditism, and Wilms' tumor. Incomplete forms of the Syndrome have been described. Germline WT1 missense mutations located in exons 8 or 9 coding for zinc fingers 2 or 3 have been detected in nearly all patients with Denys-Drash Syndrome and in some patients with isolated diffuse mesangial sclerosis. Patients with Frasier Syndrome present with normal female external genitalia, streak gonads, XY karyotype and progressive nephropathy with proteinuria and nephrotic Syndrome with focal and segmental glomerular sclerosis progressing to end-stage renal disease in adolescence or young adulthood. They frequently develop gonadoblastoma. Germline intronic mutations leading to the loss of the +KTS isoforms have been observed in all patients with Frasier Syndrome. The same mutations have been observed in genetically female patients with isolated FSGS. Transmission of the mutation is possible. Frasier mutations have also been reported in children with Denys-Drash Syndrome.
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Gonad development in Drash and Frasier Syndromes depends on WT1 mutations.
Arkhiv patologii, 2003Co-Authors: Francis Jaubert, Vorel Vasiliu, Natacha Patey-mariaud De Serre, F. Auber, Cécile Jeanpierre, Marie-claire Gubler, Claire Nihoul-fékété, Marc FellousAbstract:The study of the gonads of 8 cases of Drash Syndrome (6 ambiguous males, 2 females) and of 2 Frasier Syndrome shows that WT1 mutations gives a dysgenetic testis which is the cause of the genital ambiguity observed at birth. By contrast the same mutations have no effect on ovary development giving normal females. However intron mutations in KTS with isoforms imbalance of WT1 proteins cause streak gonads with a female phenotype in XY patients. In consequence WT1 mutations are the cause of a spectrum of male genital malformations associated with glomerulonephritis and tumors. The absence of WT1 protein detection in sertoli cells shown by immunohistochemistry for 3 cases suggests an imprinting effect of the normal WT1 allele promotor rather than a low level of protein production. A caryotype is mandatory for a correct diagnosis.
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Two Splice Variants of the Wilms' Tumor 1 Gene Have Distinct Functions during Sex Determination and Nephron Formation
Cell, 2001Co-Authors: Annette Hammes, Marie-claire Gubler, Jian-kan Guo, Gudrun Lutsch, Joerg-robert Leheste, Danilo Landrock, Ulrike Ziegler, Andreas SchedlAbstract:Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier Syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.
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Genetics of the nephrotic Syndrome.
Current opinion in pediatrics, 2000Co-Authors: Rémi Salomon, Marie-claire Gubler, Patrick NiaudetAbstract:There are a large number of glomerular diseases that may be responsible for a nephrotic Syndrome, the most frequent in childhood being minimal change disease. In the past few years, the molecular genetic basis of several conditions that may cause a nephrotic Syndrome have been identified. Denys-Drash Syndrome and Frasier Syndrome are related diseases caused by mutations in the WT1 gene. Familial forms of idiopathic nephrotic Syndrome with focal and segmental glomerular sclerosis/hyalinosis have been identified with an autosomal dominant or recessive mode of inheritance and linkage analysis have allowed to localize several genes on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital nephrotic Syndrome has been identified. This gene, named NPHS1, codes for nephrin, which is located at the slit diaphragm of the glomerular podocytes and is thought to play an essential role in the normal glomerular filtration barrier.
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donor splice site mutations in wt1 are responsible for Frasier Syndrome
Nature Genetics, 1997Co-Authors: Sandrine Barbaux, Francis Jaubert, Marie-claire Gubler, Patrick Niaudet, Jeanpierre Grunfeld, F Kuttenn, Claire N Fekete, N Souleyreautherville, E Thibaud, Marc FellousAbstract:Frasier Syndrome (FS) is a rare disease defined by male pseudo-hermaphroditism and progressive glomerulopathy1–3. Patients present with normal female external genitalia, streak gonads and XY karyotype4 and frequently develop gonadoblastoma1,2,5,6. Glomerular symptoms consist of childhood proteinuria and nephrotic Syndrome, characterized by unspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood4. No case of Wilms′ tumour has been reported, even in patients with extended follow-up1–5. In contrast with FS patients, most individuals with Denys-Drash Syndrome (DOS; refs 6,7) have ambiguous genitalia or a female phenotype, an XY karyotype and dysgenetic gonads. Renal symptoms are characterized by diffuse mesangial sclerosis, usually before the age of one year, and patients frequently develop Wilms′ tumour8–9. Mutations of the Wilms′-tumour gene, WT1, cause different pathologies of the urogenital system, including DDS10–12. WT1 is composed of ten exons and encodes a protein with four zinc-finger motifs and transcriptional and tumoursuppressor activities13–15. Alternative splicing generates four isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of three amino acids (KTS) between the third and fourth zinc fingers of WT1 (ref. 17). Here we demonstrate that FS is caused by mutations in the donor splice site in intron 9 of WT1, with the predicted loss of the +KTS isoform. Examination of WT1 transcripts indeed showed a diminution of the +KTS/-KTS isoform ratio in patients with FS.
Cgd Brook - One of the best experts on this subject based on the ideXlab platform.
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Frasier Syndrome part of the denys drash continuum or simply a wt1 gene associated disorder of intersex and nephropathy
Clinical Endocrinology, 2000Co-Authors: Ania Koziell, Evangelia Charmandari, Peter C. Hindmarsh, Lowell Rees, Peter J. Scambler, Cgd BrookAbstract:Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumorigenesis and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys-Drash Syndrome is well described. More recently WT1 mutations have also been described in a related condition, Frasier Syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier Syndrome: a 1228 + 5 guanine to adenine substitution at the 3' alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier Syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.
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Frasier Syndrome, part of the Denys Drash continuum or simply A WT1 gene associated disorder of intersex and nephropathy?
Clinical endocrinology, 2000Co-Authors: Ania Koziell, Evangelia Charmandari, Peter C. Hindmarsh, Lowell Rees, Peter J. Scambler, Cgd BrookAbstract:Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumourigenesis [corrected] and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys-Drash Syndrome is well described. More recently WT1 mutations have also been described in a related condition, Frasier Syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier Syndrome: a 1228 + 5 guanine to adenine substitution at the 3' alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier Syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.
Ania Koziell - One of the best experts on this subject based on the ideXlab platform.
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Frasier Syndrome part of the denys drash continuum or simply a wt1 gene associated disorder of intersex and nephropathy
Clinical Endocrinology, 2000Co-Authors: Ania Koziell, Evangelia Charmandari, Peter C. Hindmarsh, Lowell Rees, Peter J. Scambler, Cgd BrookAbstract:Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumorigenesis and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys-Drash Syndrome is well described. More recently WT1 mutations have also been described in a related condition, Frasier Syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier Syndrome: a 1228 + 5 guanine to adenine substitution at the 3' alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier Syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.
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Frasier Syndrome, part of the Denys Drash continuum or simply A WT1 gene associated disorder of intersex and nephropathy?
Clinical endocrinology, 2000Co-Authors: Ania Koziell, Evangelia Charmandari, Peter C. Hindmarsh, Lowell Rees, Peter J. Scambler, Cgd BrookAbstract:Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumourigenesis [corrected] and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys-Drash Syndrome is well described. More recently WT1 mutations have also been described in a related condition, Frasier Syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier Syndrome: a 1228 + 5 guanine to adenine substitution at the 3' alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier Syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.
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Frasier Syndrome is caused by defective alternative splicing of wt1 leading to an altered ratio of wt1 kts splice isoforms
Human Molecular Genetics, 1998Co-Authors: Barbara Klamt, Ania Koziell, Peter J. Scambler, Philippe Berta, Francis Poulat, Peter Wieacker, Manfred GesslerAbstract:The Wilms' tumor gene WT1 plays a key role in genitourinary development and subsequent normal function, Homozygous mutations of WT1 can be found in similar to 15% of Wilms' tumors, Furthermore, somatic heterozygous loss of WT1 is known to lead to cryptorchidism and hypospadias in males, A much more severe phenotype is seen in patients with Denys-Drash Syndrome which results from heterozygous dominant-negative mutations of the gene, Characteristic features are mesangial sclerosis with early kidney failure, varying degrees of gonadal dysgenesis and high risk of Wilms' tumors, Here we show that a related disease, Frasier Syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide, Disruption of alternative splicing at the exon 9 splice donor site prevents synthesis of the usually more abundant WT1 +KTS isoform from the mutant allele, In contrast to Denys-Drash Syndrome, no mutant protein is produced, The splice mutation leads to an imbalance of WT1 isoforms in vivo, as detected by RT-PCR on streak gonadal tissue, Thus, WT1 isoforms must have quite different functions, and the pathology of Frasier Syndrome suggests that especially gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform.
Etienne Berard - One of the best experts on this subject based on the ideXlab platform.
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A novel Wilms’ tumor 1 gene mutation in a child with severe renal dysfunction and persistent renal blastema
Pediatric Nephrology, 2008Co-Authors: Nicole Wagner, Andreas Schedl, Kay-dietrich Wagner, Mickael Afanetti, Fabien Nevo, Corinne Antignac, Jean-francois Michiels, Etienne BerardAbstract:The Wilms’ tumor suppressor gene WT1 is an important regulator of development. Mutations in this gene have been associated with Wilms’ tumor, Frasier Syndrome, and Denys–Drash Syndrome, as well as isolated glomerular disease. Here we report the case of a 4-month-old girl, who presented with end-stage renal disease, thrombopenia, anemia, and cardiac hypertrophy accompanied by severe hypertension. Histological analysis of kidney biopsies revealed a massive and diffuse nephroblastomatosis with a dramatic reduction in the number of glomeruli. Although no normal cortical nephrons could be detected, medullary organization was nearly normal. Sequence analysis demonstrated a heterozygous nonsense mutation in exon 9 of WT1 , which leads to a truncation of the WT1 protein at the beginning of zinc finger 3. Given the requirement of WT1 for normal development of the kidney and heart, these data raise the hypothesis that the mutation identified was responsible for the severe phenotype observed in our patient.
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A novel Wilms’ tumor 1 gene mutation in a child with severe renal dysfunction and persistent renal blastema
Pediatric nephrology (Berlin Germany), 2008Co-Authors: Nicole Wagner, Andreas Schedl, Kay-dietrich Wagner, Mickael Afanetti, Fabien Nevo, Corinne Antignac, Jean-francois Michiels, Etienne BerardAbstract:The Wilms' tumor suppressor gene WT1 is an important regulator of development. Mutations in this gene have been associated with Wilms' tumor, Frasier Syndrome, and Denys-Drash Syndrome, as well as isolated glomerular disease. Here we report the case of a 4-month-old girl, who presented with end-stage renal disease, thrombopenia, anemia, and cardiac hypertrophy accompanied by severe hypertension. Histological analysis of kidney biopsies revealed a massive and diffuse nephroblastomatosis with a dramatic reduction in the number of glomeruli. Although no normal cortical nephrons could be detected, medullary organization was nearly normal. Sequence analysis demonstrated a heterozygous nonsense mutation in exon 9 of WT1, which leads to a truncation of the WT1 protein at the beginning of zinc finger 3. Given the requirement of WT1 for normal development of the kidney and heart, these data raise the hypothesis that the mutation identified was responsible for the severe phenotype observed in our patient.
